Soft tissue sarcomas are tumors of the connective tissue that can arise anywhere in the body and is fatal in nearly 1/3 of patients. Myxoid liposarcoma (MLPS) is a type of malignant sarcoma that accounts for 1/3 of all liposarcomas, the most common soft tissue sarcoma. Clinically, MLPS has two unique properties. First, they have been observed to be more radiosensitive compared to other sarcomas, which are mostly radioresistant. Second, these tumors metastasize to bone, liver, and other soft tissue sites rather than to the lung, the most common site of metastasis for sarcomas. Genetically, MLPS is characterized by a t (12;16)(q13;p11) translocation in humans. Previous studies have shown that the translocation produces a fusion oncoprotein, FUS- CHOP, which is sufficient to induce MLPS in mice. How FUS-CHOP drives tumorigenesis remains unclear, and whether FUS-CHOP contributes to the distinctive radiosensitivity of MLPS is unknown. To most accurately model human disease, here I apply CRISPR-Cas9 technology for genome editing to generate a rapid, tempo- rally and spatially restricted mouse model of MLPS with the Fus-Chop translocation at the endogenous locus. The long-term goal of this project is to elucidate and harness mechanisms of radiosensitivity to radiosensitize cancers. The overall goal of this proposal is to dissect the mechanisms by which Fus-Chop mediates tumor- igenesis and radiosensitivity in MLPS. These processes will be studied by using CRISPR/Cas9 technology in vitro and in vivo to generate the Fus-Chop translocation. The central hypothesis of this study is that Fus-Chop creates a radiosensitive phenotype by modifying the ER stress and DNA damage responses. Using in vitro and in vivo systems generated with CRISPR/Cas9, I will test this hypothesis in the following three specific aims: Aim 1: Elucidate the mechanisms of Fus-Chop in tumorigenesis of MLPS via CRISPR/Cas9-mediated chromosomal rearrangements in vitro. Aim 2: Determine the role of Fus-Chop in modifying cellular response to ER stress and ionizing radiation. Aim 3: Determine the role of Fus-Chop in mediating response to radiotherapy in a primary mouse model of MLPS using CRISPR/Cas9 technology. I will define the role of Fus-Chop in the radiation response of MLPS and also generate a valuable radiosensitive pre-clinical model for radiation oncology.